Phase II Trial of Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized With NFKB2 Rearrangement. (Proteasome Inhibitor NFKB2 Rearrangement Driven Trial, PINR)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 70
- 试验地点
- 4
- 主要终点
- The Primary Objective of the Study is to Test Whether the NFKB2 Rearrangement Can Guide the Selection of Treatment (Ixazomib Plus Dexamethasone (Id) or Ixazomib Plus Lenalidomide and Dexamethasone (IRd)) by Conducting the 3 Following Comparisons
研究概览
简要总结
This randomized phase II trial studies how well ixazomib and dexamethasone or ixazomib, dexamethasone, and lenalidomide work based on the presence of the rearrangement of a gene called nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (NFKB2) in treating patients with multiple myeloma that has returned after a period of improvement or does not respond to treatment. Ixazomib may stop the growth of cancer cells by blocking enzymes called proteasomes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lenalidomide may stimulate the immune system against cancer cells and may also prevent the growth of new blood vessels that tumors need to grow. It is not yet known whether ixazomib and dexamethasone, or ixazomib, dexamethasone, and lenalidomide are more effective in treating multiple myeloma.
详细描述
PRIMARY OBJECTIVES:
To test whether the NFKB2 rearrangement can guide the selection of treatment (ixazomib [ixazomib citrate] plus dexamethasone [Id] or ixazomib plus lenalidomide and dexamethasone [IRd]) by conducting the following comparisons:
I. To compare the response rate at 4 cycles between patients treated with Id and patients treated with IRd and confirm the lack of significant difference in overall response.
II. To compare the response rate at 4 cycles between non-rearranged and rearranged NFKB2 treated with Id and confirm that NFKB2 rearrangement is associated with reduce response rate.
III. To compare the responses rate at 4 cycles of patients with rearranged NFKB2 treated with Id or IRd and confirm that adding lenalidomide increases the response rate in this population.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care
- •Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 milli-International Units (mIU)/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide and ixazomib and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide through 90 days after the last dose of study drug; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy from the time of signing the informed consent form through 90 days after the last dose of study drug; in the event that the male patients choose to agree to practice true abstinence, this must follow the timelines detailed above; all patients assigned to the lenalidomide treatment group must be registered in and must comply with all requirements of the Revlimid Risk Evaluation and Mitigation Strategy (REMS) program
- •*A female of childbearing potential is a sexually mature woman who:
- •has not undergone a hysterectomy or bilateral oophorectomy; or
- •has not been naturally postmenopausal for at least 24 consecutive months
- •Multiple myeloma diagnosed according to standard criteria either currently or at the time of initial diagnosis
- •The patient has confirmed relapsed or refractory MM
- •For patients that relapse following a response to prior treatment with bortezomib or carfilzomib, six months must have elapsed since the last dose of treatment
- •The patient has received 1 to 3 prior lines of therapy. By definition, a single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of steroids (ie, less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days) would not be considered prior lines of therapy
- •Patients must have measurable disease defined by at least 1 of the following measurements:
- •Serum M-protein ≥ 1.0 g/dL (≥ 10 g/L) for an immunoglobulin (Ig)G myeloma, ≥ 0.1 g/dL for an immunoglobulin D (IgD) myeloma or 0.5 g/dL (≥ 5g/L) for an immunoglobulin A (IgA) myeloma
- •Urine light chain ≥ 200 mg/24 hours
- •Serum free light chain ≥ 10 mg/dL provided the free light chain (FLC) ratio is abnormal
- •Patients with oligo- or non-secretory disease must have bone marrow involvement with at least 30% plasmacytosis on aspiration
- •Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2
- •Absolute neutrophil count (ANC) ≥ 1,000/mm³
- •Platelet count ≥ 75,000/mm³; in the case that platelets are between 50,000-75,000, the patient can be enrolled if the plasma cell count in the bone marrow is superior to ≥ 50%; to meet this hematological eligibility no transfusion support and hematological growth factor are not allowed within 7 days before study enrollment
- •Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN)
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN
- •Serum creatinine ≤ 2.5 mg/dL or a calculated creatinine clearance ≥ 50 mL/min
排除标准
- •The patient is refractory to carfilzomib or bortezomib; (refractory is defined as patients who never achieved a response and progressed while on carfilzomib or bortezomib or within 60 days of completing treatment)
- •Prior treatment with any investigational proteasome inhibitor within 6 months of study entry
- •Female patients who are breast feeding or have a positive serum pregnancy test during the screening period
- •Failure to have fully recovered (ie, > grade 1 toxicity) from the reversible effects of prior chemotherapy
- •Diarrhea > grade 1 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03
- •Prior chemotherapy and/or immunotherapy within 14 days before enrollment; major surgery within 14 days before enrollment and minor surgery within 7 days prior to cycle 1 day 1
- •Radiotherapy within 14 days before enrollment; if the involved field covered ≤ 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy
- •Central nervous system involvement
- •Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment
- •Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months
- •Systemic treatment, within 14 days before the first dose of ixazomib, with strong cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort
- •Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive
- •Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially compromise the patient's ability to understand the patient information, to give informed consent, to comply with the treatment according to this protocol or complete the study
- •Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease; patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
- •Patient has ≥ grade 2 peripheral neuropathy or neuropathy with pain, regardless of grade that is seen on clinical examination during the screening period
- •Known intolerance to immunomodulatory drugs (IMiDs)
- •History of allergic reaction/hypersensitivity to any of the study medications, their analogues or excipients in the various formulations
- •Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib or lenalidomide, including difficulty swallowing
- •Participation in other clinical trials, including those with other investigational agents not included in this trial, such as monoclonal antibodies, within 30 days of the start of this trial and throughout the duration of this trial
- •Corticosteroid doses > 10 mg/day of prednisone or equivalent within 14 days prior to cycle 1 day 1
- •Autologous or allogeneic stem cell or bone marrow transplant within 3 months prior to cycle 1 day 1
- •Cytotoxic therapy within 21 days prior to cycle 1 day (D) 1
- •Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not
研究组 & 干预措施
Arm B (ixazomib and dexamethasone)
MUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A.
干预措施: Dexamethasone (Drug)
Arm B (ixazomib and dexamethasone)
MUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A.
干预措施: Ixazomib (Drug)
Arm C (ixazomib, dexamethasone, lenalidomide)
MUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A and lenalidomide PO daily on days 1-21.
干预措施: Dexamethasone (Drug)
Arm C (ixazomib, dexamethasone, lenalidomide)
MUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A and lenalidomide PO daily on days 1-21.
干预措施: Ixazomib (Drug)
Arm A (ixazomib and dexamethasone)
UNMUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone.
干预措施: Dexamethasone (Drug)
Arm A (ixazomib and dexamethasone)
UNMUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone.
干预措施: Ixazomib (Drug)
Arm C (ixazomib, dexamethasone, lenalidomide)
MUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A and lenalidomide PO daily on days 1-21.
干预措施: Lenalidomide (Drug)
结局指标
主要结局
The Primary Objective of the Study is to Test Whether the NFKB2 Rearrangement Can Guide the Selection of Treatment (Ixazomib Plus Dexamethasone (Id) or Ixazomib Plus Lenalidomide and Dexamethasone (IRd)) by Conducting the 3 Following Comparisons
时间窗: 112 days
Comparison to a historical control: The overall response rate (ORR) of each arm at 4 cycles (112 days) is compared to the historical RR of 30%. Arm A or Arm C is designed to detect an improved RR of 60% vs. 30% using Simon's 2-stage Optimum design with a power of at least 90% and an alpha error of 5%., respectively. For Arm B will achieve a power of at least 80% at the significance level of 0.05 to claim that Arm B has equivalent RR as the historical RR of 30% assuming an equivalence tolerance of +/- 20% when the true RR of Arm B is approximately 30%. Response Rate is defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
次要结局
- Time to Treatment Failure(Up to 30 months)
- Prevalence of NFKB2 Rearrangement in Relapsed/Refractory Multiple Myeloma Patients Screened in the Study.(At baseline and month 12)
- Percentage of Patients With Response at Baseline and at 12 Months(At baseline and at 12 months)
- Incidence of Adverse Events(30 days post-treatment, up to a total of 1 year)
研究者
Leon Bernal-Mizrachi
Principal Investigator
Emory University